Chronic, painful tendon conditions, known as tendinopathy, affect millions of Americans in both occupational and athletic settings. It has been speculated that tendinopathy may result from a failure to repair tendon matrix in response to repeated microinjuries by mechanical loading. However, scientific data to support this speculation are lacking. Also, in spite of intensive research on tendinopathy in recent years, it is still an open question for debate whether tendon inflammation leads to tendon degeneration that is often seen in the late stage of tendinopathy. Thus, the central hypothesis of this project is that chronic mechanical loading placed on the tendon induces microinjuries and inflammation, which leads to degenerative changes in the tendon matrix. To test this central hypothesis, we propose the following four specific aims: 1) to determine the effects of chronic mechanical loading via treadmill running on mouse tendons in vivo, specifically tendon microinjuries, infiltration of macrophages, presence of myofibroblasts, and expression of inflammatory mediators;2) to characterize the anabolic and catabolic gene and protein expression profiles of tendon fibroblasts from mice that are chronically loaded via treadmill running;3) to determine whether the continued loading of tendons with inflammation leads to additional degenerative changes in tendons in vivo;and 4) to determine whether reducing tendon inflammation improves the biological, biochemical, and biomechanical properties of tendons in vivo. Building upon our previous tendinitis research, which primarily focused on in vitro model studies, we will expand our research to animal model studies of tendinopathy. Using interdisciplinary and integrative approaches, we will investigate the developmental mechanisms of tendinopathy by characterizing changes in the anabolic and catabolic metabolisms of the tendon as well as changes in the phenotypic expression of tendon fibroblasts due to chronic mechanical loading in vivo. In addition, we will determine the effect of reducing tendon inflammation on the biological, biochemical, and biomechanical properties of the healing tendon. The scientific findings of this project will improve our understanding of the precise pathogenic processes of tendinopathy. They will also aid in devising new protocols for the clinical management of tendinopathy and in designing new preventive strategies, such as anti-inflammation therapy, to reduce the incidence of tendinopathy in the workplace as well as in athletic settings.